Gleevec, Use in GIST and Beyond

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Gleevec, Use in GIST and Beyond

• Avlin Imaeda 1/19/07
• Advisor Fred Gorelick

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Outline of Talk

• Tumorigenesis
• General
• Tyrosine kinases
• GIST
• Gleevec development
• Case Report in GIST
• Clinical Trials
• Complications/ side-effects
• Resistance
• Other Applications

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Tumorigenesis 6 Must-Have Attributes/Alterations
for a Really Bad Cancer

• Self-sufficient growth signals (Oncogenes)
• In-sensitivity to growth inhibitor signals (Tumor
  suppressor genes)
• Evasion of programmed cell death
• Limitless replication potential (Telomerase)
• Sustained angiogenesis
• Tissue invasion (I-CAMs, Integrins, proteases)
• Metastasis (I-CAMs, Integrins, proteases)

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Tumorigenesis- Mechanisms

• Traditional Pathway accumulation of genomic
  mutations- 4-7 stochastic events (Kinzler and
  Vogelstein et.al. studies of HNPCC and FAP)
• Epigenetic Alterations Cell differentiation
  pathways
• DNA hyper or hypo-methylation
• Small regulatory RNAs

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Tumorigenesis- other points

• One gene alteration may affect more than one of
  the attributes listed on the prior slide
• Most functions are encoded redundantly
• Cancer stem cells
• ? Relationship to stem cells
• ? Defined by ability to renew tumor and
  resistance to therapy as well as stem cell markers

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Tyrosine Kinases (TK)

• Catalyze transfer of ?-phosphate from ATP to
  polypeptides
• Human genome 90 TK and 43 TK-like genes
• Function regulate proliferation, survival,
  differentiation, function and motility
• Forms receptor TKs, non-receptor TKs

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Mechanisms of Activation of Normal TKs
Krause D and Van Etten R. N Engl J Med
2005353172-187
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Dysregulation of TKs in Cancer

• Constitutive activation fusion protein
• BCR-ABL tetramerization domain in BCR causes
  constitutive oligomerization thus
  autophosphorylation in CML
• Absence of juxtamembrane inhibitory domain due to
  fusion protein
• Point Mutations disrupting autoregulation
• FLT3R in AML mutations allow activity without
  ligand
• EGFR in NSCLC mutations in kinase domain increase
  sensitivity to ligand
• Aberrant expression of TK receptor or ligand
• Her-2/neu overexpression in breast CA
• PDGF (TK ligand) overexpression in
  dermatofibrosarcoma protuberans
• Decrease in factors that limit TK activity
• Impaired tyrosine phosphatase activity
• Decrease expression of TK inhibitor proteins

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Tyrosine Kinase Targets in Malignant Hematologic
Disorders
Krause D and Van Etten R. N Engl J Med
2005353172-187
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Tyrosine Kinase Targets in Solid Tumors
Krause D and Van Etten R. N Engl J Med
2005353172-187
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Gastrointestinal Stromal Tumors-GISTs

• Soft tissue sarcomas
• Origin mesenchymal stem cells in the GI tract
• 10-30 or more are malignant
• Rare before age 40
• Most in stomach (60-70) or small intestine
  (10-30) rectum and esophagus (more likely to be
  malignant) rare in colon
• Presentation often incidental, dependent on
  location
• Median survival when complete resection not
  possible10-23m
• Median survival from diagnosis of metastatic or
  recurrent disease 12-19 months
• Response of GISTs to traditional
  anthracycline-based chemotherapy only 0-5

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Genesis of a GIST

• Cell of origin precursor of Interstitial cells
  of Cahal and smooth muscle cells
• Mutations C-KIT (92) or PDGF -RA (5)
• In families with germ-line c-KIT mutations, most
  if not all develop GIST tumors (also systemic
  mastocytosis)

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GIST factors associated with lower malignancy
risks

• Gastric location
• Size lt 5cm
• Low mitotic count 1 or less per 50 HPF
• Low Ki-67 (proliferation index)
• Lack of infiltration to adjacent organs
• DNA- diploidy (G2 peak)
• /- young patient age and histologic grade

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Gleevec

• Tyrosine Kinase Inhibitor
• Bcr-Abl
• C-Kit
• PDGFR a and b

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Gleevec Development

• 1992 Okabe et.al. Blood 801330 Herbimycin A
  an antagonist of tyrosine kinase blocked growth
  of Ph cell lines in vitro
• 1993 Anafi et.al. Blood 823524 2 synthetic
  tyrosine kinase competitive inhibitors block
  proliferation of Bcr-Abl cell line in vitro
• 1996 Drucker et.al. Oregon Health Sciences and
  Ciba Pharmaceuticals Nat Med 2561 Develop CGP
  57148 designed to bind the ATP binding site of
  protein kinases. The molecule blocked tumor
  formation in mice by Bcr-Abl cells and blocked
  colony formation by cells from CML patients

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Gleevec Development Cont.

• 8/2000 Heinrich et.al. Blood 96925 STI 571
  (formerly CGP 57148) shown to inhibit c-kit
  tyrosine kinase activity in vitro
• 4/2001 Druker et.al. NEJM 3441031 Phase I
  clinical trial of STI 571 in chronic phase CML
  shows complete hematologic response in 53/54,
  cytogenetic response in 29/54 and complete
  cytogenetic response in 7/54, no maximum
  tolerated dose identified, adjacent article
  showed less response or rapid relapse in blast
  crisis CML or PH ALL
• 4/2001 Joensuu et.al. NEJM 3441052 Case report
  showing activity of STI 571 (soon to be Imatinib
  Mesylate or Glivec or Gleevec) against GIST in a
  patient

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First Case ReportJoensuu et.al. (2001) NEJM
3441052

• 50 y/o previously healthy woman presented 10/96
  with abdominal pain and was found to have 2
  tumors 6.5 cm and 10 cm in size which were
  resected from the stomach along with greater
  omentum and mesocolic peritoneum which contained
  multiple mets
• 2/98 and 9/98 8 liver mets, mult intra-abdominal
  mets and ovarian mets were excised
• 11/98-3/99 given 7 cycles mesna, doxorubicin,
  ifosfamide, dacarbazine for liver mets without
  clinical response
• 3/99 removal of large obstructing met and 45
  smaller mets
• 4/99-2/00 treated with thalidomide and sc
  interferon-alpha tid

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First Case ReportJoensuu et.al. (2001) NEJM
3441052

• 2/00 liver metastases progressing with several
  new intra-abdominal and mesenteric mets on MRI
• Patient agreed to participate in trial of Gleevec
• Tumor was CD117 (c-KIT) positive and analysis
  revealed 15 bp deletion from exon 11 of c-KIT
• She was treated with 400 mg qd Gleevec (Imatinib
  Mesylate)

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Transaxial Gadolinium-Enhanced T1-Weighted MRI
Studies of the Upper Abdomen
T 0 112.5 cm2 2 wks 67 cm2 2 mos 54 cm2 4 mos
36 cm2 5.5 mos 33 cm2 8 mos 28 cm2 No new
lesions 6/28 liver mets disappeared
4 weeks treatment Less peripheral
enhancement Consistent with more cystic
appearance
8 months treatment
Joensuu H et al. N Engl J Med 20013441052-1056
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PET Studies with 18FFluorodeoxyglucose as the
Tracer
Before Treatment
After 4 weeks Treatment
Joensuu H et al. N Engl J Med 20013441052-1056
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Histologic Appearance of the Primary
Gastrointestinal Stromal Tumor (Hematoxylin and
Eosin Panels A, B, and C and Immunostaining for
Ki-67 Panels D and E and CD117 Panels F and G)
Joensuu H et al. N Engl J Med 20013441052-1056
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Clinical TrialsDagher et.al. (2002) Clin Can Res
FDA Approval Summary

• 1 European Center, 3 U.S. Centers
• 73 Pts randomized to 400 mg imatinib
• 74 Pts randomized to 600 mg imatinib
• No control group
• Eligibility metastatic and/or unresectable
  CD117 GIST
• Exclusion for performance status, chemo within 4
  weeks or significant radiotherapy
• Endpoint objective tumor response (partial
  response, PR by SWOG )
• Duration of exposure at termination, 76 lt or
  6mos, 24 6 mos to 12 mos

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Clinical TrialsDagher et.al. (2002) Clin Can Res
FDA Approval Summary
Table 1 Tumor response by dose
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Clinical TrialsDagher et.al. (2002) Clin Can Res
FDA Approval Summary

• 1/56 Pts with documented disease progression by
  the cutoff date, despite protocol, the Pt
  remained on treatment and had subsequent PR

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Clinical TrialsVerweij et.al. (2003) Eur J of
Cancer 392006

• 27 GIST and 24 other soft tissue sarcomas (STS)
  entered, phase II trial
• Eligibility advanced and/or metastatic CD117
  GIST any other subtype of STS incurable by
  surgery or radiotherapy (excluding mesothelioma,
  chondrosarcoma, neuroblastoma, osteossarcoma,
  Ewings sarcoma and embryonal rhabdomyosarcoma)
• Measurable lesion with evidence of progression
  within 6 weeks prior to entry
• Some prior chemo restrictions
• Other performance status and lab criteria

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Clinical TrialsVerweij et.al. (2003) Eur J of
Cancer 392006
                                             
Fig. 2. Time to progression, by histology GIST
versus other soft-tissue sarcomas (STS).
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Determining Response GIST characteristics

• PET scan response observed in as little as 24 hrs
  (generally only used in clinical trials,
  predicted 1 yr survival in 1 trial)
• GISTs may increase in size early in treatment due
  to intratumoral hemorrhage or myxoid degeneration
  
• CT shows decrease density with hemorrhage or
  degeneration prior to decrease size
• Survival in stable disease equivalent to that in
  patients with objective response

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Determining Response

• RECIST criteria (Response Evaluation Criteria in
  Solid Tumors)
• Partial response 30 decrease in longest
  dimension each measurable deposit
• Minor response 10-30 reduction
• Stable disease 10 reduction to 20 increase
• Progressive gt20 increase or new lesions
• Choi criteria 10 decrease in unidimensional
  tumor size or 15 decrease in tumor density on
  contrast CT
• Comparison 98 patients (5 yrs) 48 good
  responders by RECIST, 84 good responders by Choi
  at 8 wks. Choi criteria and PET correlated with
  survival (DSS) (p0.04) whereas RECIST did not
  (p0.45) .

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Complications/ Side-effects

• Phase I trials, no maximum tolerated dose

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Report to the FDA Dagher et.al. (2002) Clin Can
Res 83034
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Complications/ Side-EffectsSummary

• Bleeding generally grade 1 to 2, not related to
  tumor burden
• Nausea/ vomiting improved by taking with meals
• Flatulence, abdominal discomfort, diarrhea
  diarrhea usually grade 1-2 occasionally more
  severe, often responds to immodium
• Muscle cramps bothersome long-term symptom
• Skin rash usually mild and usually resolves
• Cytopenias rarely significant with GIST
• Edema periph edema common, esp peri-orbital,
  grade 3 to 4 about 1.3
• Cardiac toxicity severe heart failure reported
  in 10 patients, monitoring for signs and symptoms
  recommended

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Side-Effects Mechanisms

• Bleeding ?PDGF, ? Relationship to tumor bulk
• Cardiac Toxicity
• Kerkela et.al. (2006) Nature Med 12908
• Abnormalities in mitochondria and ER in 6 humans
  and treated mice
• Gleevec activates ER stress response
• Gene transfer of Gleevec resistant c-Abl or
  inhibition of JNK rescues cells

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Resistance

• What Determines Susceptibility
• Site of Mutation
• Dependence of tumor on the TK (dependent- BCR-ABL
  CML, GIST, Hypereosinophilic syndrome,
  dermatofibrosarcoma protuberans)
• Late resistance
• Secondary mutations
• Stem cells

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Table 1. KIT and PDGFRA Genotype Versus Clinical
Response in the CSTI571B 2222 Phase II Trial
Henrich et.al. (2003) J of Clin Oncol 214342
Nonassessable
Progressive Disease

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Mechanisms of Resistance to TK-Inhibitor Therapy
Krause D and Van Etten R. N Engl J Med
2005353172-187
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Resistance Stem CellsCML BCR/ABL CD34
CD38-Copland et.al. (2006) Blood 1074532

• Stem Cell Specific (BCR/ABL Independent
  Resistance)
• Insufficient drug levels (altered influx/efflux)
• Gene amplification, high transcript, kinase
  activity
• Altered switch between active and inactive
  BCR/ABL conformation (Gleevec only binds inactive
  form)
• Enrichment in stem cells of mutations in kinase
  domains that prevent binding

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Limitations

• No complete responses in GIST
• Resistance/ Stem Cells
• Cardiac Toxicity
• ?Duration of Treatment

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Future many drugs in development eg. Sunitinib

• Sunitinib KIT, PDFGRs, VEGFRs, RET, FLT3
• Efficacy against Gleevec resistant GIST
• Heinrich et.al. (2006) J Clin Onc 2418S9502-
  evaluated tumor mutations and Sunitinib response
  in Gleevec resistant patients exon 9 gt exon 11
  mutations
• secondary KIT mutations in GISTS with exon 11gt
  exon 9, no secondary mutations in patients
  lacking primary KIT/PDGFRA mutation

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Future Dasatinib

• Binds both active and inactive BCR-ABL
• Binds many Imatinib resistant mutations including
  D816Y seen in AML and some systemic mastocytosis,
  and seminoma
• Appears to irradicate an earlier progenitor than
  Imatinib
• CML stem cells still resistant

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Other Applications Gleevec

• Diabetes
• Letter to the Ed, improved DM 6/7 CML Pts Breccia
  et.al. (2007) J. Clin Oncol 224653
• In vitro data showing Bcr-Abl affects glucose
  metabolism (multiple articles, also usage in PET)
• Atherosclerosis
• Gleevec reduces atherosclerosis in mouse models
  where PDGFR or PDGF is upregulated ie DM or LRP1
  k/o Lassila et.al. (2004) Arterioscler Thromb
  Vasc Biol 24935 Boucher et.al. (2003) Science
  300 329

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Other Applications of Gleevec

• Fibrosis PDGF in Lung, Liver, Kidney
• Gleevec blocks bleomycin induced lung fibrosis
  in mice, proliferation of mesenchyme not early
  inflammation, role of PDGF and Abl suggested Aono
  et.al.(2005) Am J Resp Crit Care Med 1711279,
  Daniels et.al. (2004) J. Clin. Invest. 1141308
• Gleevec blocks irradiation induced pulmonary
  fibrosis in mice Abdollahi et.al. (2005) JEM
  201925
• Letter/case report Gleevec improved NYHA
  function in man with familial IPF failing
  bosentan, inh iloprost and sildenafil Ghofrani
  et.al. (2005) NEJM 3531412
• Gleevec block liver fibrosis in 3 rat models of
  liver fibrosis, CCL4, BDL and pig serum-induced
  Yoshiji et.al. (2006) Int J Mol Med 17899 Neef
  et.al. (2006) J. Hepat 44167 Yoshiji et.al.
  (2004) Am J Physiol Gastrointest Liver Physiol
  2886907
• Innate Immunity Gleevec may stimulate NK cells
  independent of its action on GIST cells Borg
  et.al. (2004) 114379

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Thank You!

• Dr. Gorelick

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Anti-Helpers
I Want Special Treats, She Demanded!
NO, NO, NO!